Preparation of phenoxybenzyl esters

ABSTRACT

Phenoxybenzyl esters are prepared by neutralizing an aqueous solution of a carboxylic acid and contacting the neutralized solution with a solution of phenoxybenzyl halide in a water-immiscible base in the presence of a phase transfer catalyst.

This is a division of application Ser. No. 737,312, filed Nov. 1, 1976,now U.S. Pat. No. 4,061,664.

FIELD OF THE INVENTION

This invention relates to an improved process for preparingphenoxybenzyl esters of cyclopropane carboxylic acids or phenylaceticacids, these compounds being very active as pesticides and forming partof the group of compounds known as "synthetic pyrethroids".

SUMMARY OF THE INVENTION

Accordingly the present invention provides a process for the preparationof a phenoxybenzyl ester of formula (I) ##STR1## wherein an acid offormula R--COOH in which R represents an optionally substitutedcyclopropyl group or an optionally substituted benzyl group isneutralized with a water-soluble base, and then contacted with asolution in a substantially water-immiscible organic solvent of a benzylhalide of formula ##STR2## in which X represents a halogen, preferablychlorine or bromine, atom; and Q represents a hydrogen atom or cyanogroup in the presence of a phase-transfer catalyst.

The neutralisation of the aqueous acid solution can be effected by theuse of any water-soluble base, but for reasons of convenience andeconomics it is usually preferred to use an inorganic base such aspotassium carbonate or hydroxide or sodium hydroxide.

Although any substantially water-immiscible organic liquid maytheoretically be used as solvent for the benzyl halide, it is generallypreferable to use an organic liquid in which the benzyl halide is atleast moderately soluble. Furthermore, eventual recovery of the esterproduct is often simplified if the organic liquid solvent is lighterthan water. Suitable solvents include aromatic hydrocarbons such asbenzene and toluene or petroleum ether, and it may be convenient to usemixed with hydrocarbons such as xylenes, trimethylbenzene or kerosene asthe benzyl halide solvent since the resulting solution of ester can thenbe employed directly, without isolation of the ester, in the productionof a pesticidal emulsifiable concentrate. The reactant solutions arecontacted with each other as by agitating, stirring or the like.

The phase-transfer catalyst may be any reagent which will accelerateinterphase reactions in aqueous/organic two-phase systems, the mostconvenient such catalysts including quaternary ammonium and phosphoniumsalts. Generally economic considerations make it preferable to usequaternary ammonium salts. The quaternary ammonium salts have fourhydrocarbyl groups--which optionally may be substituted--attached to thenitrogen atom, for example, aromatic, aliphatic, cycloaliphatic orunsaturated groups or combinations of any of these groups, for examplean aromatic-aliphatic group. The cation of the tetrahydrocarbylammoniumsalt may contain one or more quaternary bound nitrogen atoms. The saltmay have any anion; chlorides and bromides are preferred. The totalnumber of carbon atoms in the four hydrocarbyl groups is preferably from12 to 70. Examples of suitable tetrahydrocarbylammonium salts aretetraalkylammonium halides such as tetra-n-butylammonium chloride,tetra-n-pentylammonium chloride, ethyl-tri-sec-octylammonium chloride,ethyl-tri-n-hexylammonium chloride, n-hexadecyltri-n-hexylammoniumchloride, di-n-undecyldiethylammonium chloride and tetra-n-octylammoniumchloride, or aryltrialkylammonium halides such asbenxyltri-n-butylammonium chloride and the corresponding bromides. Thecorresponding phosphonium compounds are also useful. Tetra-alkylammonium halides are particularly preferred. Alternatively, themacrocyclic polyethers known as "crown ethers" may be utilized as phasetransfer catalyst. These compounds, together with their preparation, aredescribed in the literature, for example in Tetrahedron Letters No. 18(1972) pp. 1793-1796, and are commonly designated by reference to thetotal number of atoms forming the macrocyclic ring together with thenumber of oxygen atoms in that ring. Thus the macrocyclic polyetherwhose formal chemical name is 1,4,7,10,13,16-hexaoxacyclooctadecane isdesignated as "18-crown-6". Further suitable macrocyclic polyethers aredescribed in U.S. Pat. No. 3,562,295, British Pat. No. 1,108,921 and inco-pending British patent application No. 10,744/75. Other types ofcompound which may be used as the phase-transfer catalyst includequaternary ammonium anion exchange resins (suitably in the hydroxylform) as shown for example in U.S. Pat. No. 3,917,667.

The concentration of catalyst used may vary widely, but at lowconcentrations (e.g. 1 mole % or less) a higher reaction temperature isrequired to complete the esterification reaction within an acceptableperiod of time, whilst the use of higher concentrations (e.g. above 10mole %) naturally increases the cost of the catalyst required to producea given quantity of ester. For example, the use of 5 mole % of catalystat 65°-70° C. will lead to a 20-30 fold reduction in reaction time ascompared with the same reagent concentrations at room temperature, andreduction of the catalyst concentration to 1 mole % increases thereaction time 2-3 fold. Thus, the choice of reaction temperature andcatalyst concentration are mutually interdependent, and in anyindividual instance will depend on the local economic factors.

In the phenoxybenzyl esters of formula (I), R is preferably

(i) a cyclopropyl group of formula (III) ##STR3## wherein R_(a) andR_(b) each represent an alkyl group having from 1 to 6 carbon atoms,especially methyl, or a halogen atom of atomic number 9-35, inclusive,especially a chlorine atom; or R_(a) and R_(b) together represent analkylene group having from 2 to 6, especially 3, carbon atoms; or R_(a)represents a hydrogen atom and R_(b) represents an alkenyl group havingfrom 2 to 6 carbon atoms, especially an isobutenyl group, or anhaloalkenyl group having from 2 to 6 carbon atoms and from 1 to 3chlorine or bromine atoms, especially a mono- or dichlorovinyl group;R_(c) and R_(d) each represent an alkyl group having 1 to 6 carbonatoms, especially methyl, or R_(c) is hydrogen and R_(d) is an alkenylgroup having from 2 to 6 carbon atoms, especially an isobutenyl group,or an haloalkenyl group having from 2 to 6 carbon atoms and from 1 to 3chlorine or bromine atoms, especially a mono- or dichlorovinyl group; orR_(c) and R_(d) together represent an alkylene group having from 2 to 6,especially 3 carbon atoms; or

(ii) a benzyl group of formula (IV) ##STR4## wherein Z represents ahalogen atom of atomic number 9-35, inclusive, preferably a chlorineatom, or an alkoxy group of 1 to 4 carbon atoms, e.g. methoxy, and Yrepresents an alkyl group of 1 to 6 carbon atoms, especially a branchedchain group such as an isopropyl group. The phenoxy substituent in thephenoxybenzyl esters of general formula (I) is preferably in the3-position.

It will be appreciated that as a result of the asymmetric carbon atomsand double bonds which may be present in the phenoxybenzyl estersprepared by the process according to the present invention, the esterscan exist in a number of stereoisomeric forms and therefore the presentinvention also extends to the production of any one or a mixture of suchstereoisomers. The required stereoisomer or mixture of stereoisomers maybe obtained by using as starting material the appropriate stereoisomericcarboxylic acid and/or the appropriate stereoisomeric phenoxybenzylhalide.

The process of this invention is of particular value in its applicationto the preparation of alpha-cyano-3-phenoxybenzyl esters oftetramethylcyclopropane carboxylic acid,dimethyl-dichlorovinyl-cyclopropane carboxylic acid,dimethyl-dibromovinyl-cyclopropane carboxylic acid and2-(4-chlorophenyl)-3-methylbutyric acid, because these esters haveinteresting pesticidal, especially insecticidal, activity.

In this application the process offers certain advantages over aconventional esterification process using no phase-transfer catalyst.Thus, for example, a conventional process normally produces significantamounts of impurities (such as the olefin formed by hydrogen halideelimination between 2 molecules of benzyl halide) whose removal requiresan expensive crystallisation procedure. Use of the phase-transfercatalyst according to the present invention yields a product lesscontaminated with these impurities. Furthermore, use of thephase-transfer catalyst also facilitates operation of the process athigher reactant concentrations and because the organic solvent used forthe benzyl halide can be the same as that required in a pesticidalemulsifiable concentrate, it is possible, using the process of thisinvention, to produce the final ester as an organic solution which canbe transformed directly (i.e. without any further work-up) into apesticidal emulsifiable concentrate by the addition of appropriatesurfactants.

The invention is illustrated in the following Examples.

EXAMPLE 1

A solution of 2,2,3,3-tetramethylcyclopropane carboxylic acid (470g;3.3M) in water (1200 ml) and potassium carbonate (228g; 1.65M) wastreated with a solution of alpha-cyano-3-phenoxybenzyl bromide (864g;3.0M) in toluene (1500 ml) and the phase-transfer catalyst,tetrabutylammonium bromide, (48g; 5 mole %). The mixture was vigorouslystirred and heated to 30° C. The rate of reaction and the completion wasdetermined by thin layer chromatography using Merck pre-coated plates(silica-gel 60F-254), developed in the following solvent mixture: ethylacetate 1 vol, chloroform 2 vols. and hexane 7 vols. The reaction wascontinued until no benzyl bromide could be detected by U.V. light.

When the reaction was complete (after about 24 hours), the aqueous phasewas separated and the toluene solution washed with 5% aqueous potassiumcarbonate solution (2 × 1 liter portions), water (2 × 1 liter portions),and then filtered through a pad of silica-gel (100g). The solution wasevaporated under reduced pressure and degassed under high vacuum (0.1mmHg at 50° C.) to give the crude product (1070g, purity 92%). The crudeproduct was up-graded by dissolving in methanol (2 liters) andcrystallised with stirring and cooling. A filter-stick was then insertedand the mother-liquors (1230 ml) removed by suction. The residual solidin the reactor was melted, evaporated, and finally degassed under highvacuum to give alpha-cyano-3-phenoxybenzyl2,2,3,3-tetramethylcyclopropane carboxylate (953g, purity = 95%).

Yield purified product was 86.4% based on starting benzyl bromide.

EXAMPLE 2

A mixture of 2,2,3,3-tetramethylcyclopropane carboxylic acid (7.8g,0.055M), potassium carbonate (3.8g, 0.0275M) water (40 mls),tetrabutylammonium bromide (1.5g, 10 mole %),alpha-cyano-3-phenoxybenzyl bromide (14.4g, 0.05 mole) and toluene (50ml) was stirred at 25° C. for 5 hours. The aqueous phase was separatedand the toluene layer washed twice with 5% potassium carbonate solutionand twice with water. The solution was filtered through a pad ofsilica-gel (3g) and evaporated to leave a pale-yellow oil (17.4g; purity= 92%). Recrystallisation of this material from hexane gave purealpha-cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclopropane carboxylate,melting point 50°-51° C.

Similar experiments carried out at different temperatures and usingdifferent concentrations of phase-transfer catalyst showed that completereaction required 1 hour at 65° C. for a 5 mole % catalyst or 3 hours at70° C. for 1 mole % catalyst.

EXAMPLE 3

A mixture of 2-(4-chlorophenyl)-3-methylbutyric acid (703g, 3.3M), water(1500 ml), potassium carbonate (228g, 1.65M) and tetrabutylammoniumbromide (48g, 5 mole %) was treated with a solution ofalpha-cyano-3-phenoxybenzyl bromide (864g, 3.0M) in toluene (1500 ml).The mixture was vigorously stirred and heated to 35° C. The rate ofreaction was followed and completion determined by thin layerchromatography using Merck pre-coated plates (silica-gel 60 F-254),developed in a solvent mixture of ethyl acetate 1 vol., chloroform 2vols., hexane 7 vols. The reaction was continued until no bromonitrilecould be detected by U.V. light.

When the reaction was complete (about 60 hours), the aqueous phase wasseparated and the toluene layer washed with 5% aqueous potassiumcarbonate (2 × 1 liter portions), water (2 × 1 liter portions) and thenfiltered through a pad of silica-gel (100g).

The resulting solution was evaporated under reduced pressure and finallydegassed under high vacuum (0.1 mm Hg at 50° C.) to givealpha-cyano-3-phenoxybenzyl-2-(4-chlorophenyl)-3-methyl butyrate (1258g;purity = 98%).

Yield based on benzyl bromide was 98%.

EXAMPLE 4

A mixture of 2-(4-chlorophenyl)-3-methylbutyric acid (11.68g, 0.055M),potassium carbonate (3.79g, 0.0275M), water (50 ml),alpha-cyano-3-phenoxybenzyl bromide (14.4g, 0.05M), toluene (50 ml), andtetrabutylammonium bromide (1.5g, 10 mole %) was stirred for 24 hours at25° C. and worked up as for Example 3.

The desired product was isolated as a bottom oil in yield of 97% andpurity of 96%.

EXAMPLE 5

Example 4 was repeated using the same reactants in the same quantities,except that only 0.15g (1 mole %) of tetrabutylammonium bromide wasused. Essentially quantitative yield of the desired product was obtainedafter 5 hours at 70° C.

EXAMPLE 6

Example 4 was repeated using the same reactants in the same quantitiesexcept that 0.75g (5 mole %) of tetrabutylammonium bromide was used.Essentially quantitative yield of the desired product was obtained after2 hours at 65° C.

EXAMPLE 7

A mixture of 2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropane carboxylicacid (11.55g, 0.055M), water (50 mls), potassium carbonate, (3.7g,0.0275M), 3-phenoxybenzyl bromide (13.15g, 0.05M), toluene (50 mls), andtetrabutylammonium bromide (0.75g, 5 mole %), was stirred at 65° C. andyielded close to quantitative yield of the desired product after about48 hours reaction time.

EXAMPLE 8

A mixture of 2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropane carboxylicacid (311g, 1.49M), water (700 mls), potassium carbonate (104g, 0.75M),alpha-cyano-3-phenoxybenzyl bromide (395g, 1.37M) toluene (700 mls) andtetrabutylammonium bromide (4.4g, 1 mole %) was stirred at 65° C. for 10hours. The product was worked-up as described in Example 3 to givealpha-cyano-3-phenoxybenzyl-2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropanecarboxylate (550g). Yield based on alpha-cyano-3-phenoxybenzyl bromidewas 96.5%.

EXAMPLE 9

A mixture of 2,2,3,3-tetramethylcyclopropane carboxylic acid (4.7kg,33M), water (12 liters), potassium carbonate (2.28kg, 16.5M),alpha-cyano-3-phenoxybenzyl bromide (8.64kg, 30M), toluene (15 liters)and tetrabutylammonium bromide (96g, 1 mole %) was stirred at 60° C. for5 hours.

A working-up procedure similar to that employed in Example 1 gavealpha-cyano-3-phenoxybenzyl-2,2,3,3-tetramethylcyclopropane carboxylate(9.280g, purity = 97%).

Yield based on starting benzyl bromide was 85.7%.

EXAMPLE 10

Example 2 was repeated using alpha-cyano-3-phenoxybenzyl chloride and 1mole % tetrabutylammonium bromide as catalyst. A similar yield of thedesired product was obtained after stirring the mixture at 90° C. for 6hours.

EXAMPLE 11

Example 6 was repeated using the same reactants in the same quantitiesexcept that 0.65g (5 mole %) of 1,4,7,10,13,16-hexaoxacyclooctadecanewas used as catalyst. The mixture was stirred at 65° C. for 20 hours andthen worked-up as previously to give the desired product in 98.2% yield.

EXAMPLE 12

Example 6 was repeated except that no catalyst was added. After 120hours at 65° C. approximately 40% of the bromide had been converted tothe desired product.

EXAMPLE 13

A mixture of cis-2,2-dimethyl-3-(2',2'-dibromovinyl)cyclopropanecarboxylic acid (2.2g, 0.0074M), water (5 mls), potassium carbonate(0.5g, 0.0037M), alpha-cyano-3-phenoxybenzyl bromide (1.94g, 0.00674M),methylene chloride (35 mls), and tetrabutylammonium bromide (0.1g, 4.6mole %) was stirred at 40° C. for 10 hours. The product was worked-up asdescribed in Example 3 to givecis-alpha-cyano-3-phenoxybenzyl-2,2-dimethyl-3-(2',2'-dibromovinyl)cyclopropanecarboxylate (3.4g, 0.00673M). Yield based on alpha-cyano-3-phenoxybenzylbromide was 99.9%.

EXAMPLE 14

Example 13 was repeated usingtrans-2,2-dimethyl-3-(2',2'-dibromovinyl)cyclopropane carboxylic acidunder the same reaction conditions and with the same quantities. Yieldof the trans-ester based on alpha-cyano-3-phenoxybenzyl bromide was100%.

EXAMPLE 15

Example 13 was repeated using (-)cis-2,2-dimethyl-3-(2',2'-dibromovinyl)cyclopropane carboxylic acidunder the same reaction conditions and the same quantities. Yield basedon alpha-cyano-3-phenoxybenzyl bromide was 100%; [α]_(D) = -11.1°.

EXAMPLE 16

A mixture of (-) 2-(4-chlorophenyl)-3-methylbutyric acid (46.75g,0.22M), potassium carbonate (15.2g, 0.11M), water (100 ml),alpha-cyano-3-phenoxybenzyl bromide (57.6g, 0.2M), methylene chloride(150 ml) and tetrabutylammonium bromide (1.3g, 2 mole %) was stirred andrefluxed for 24 hours. The desired product was isolated as a bottom oil(82.4g). Yield = 99.4%, purity = 97%; [α]_(D) = +7.3°.

I claim:
 1. A process for the preparation of a phenoxybenzyl ester offormula (I) ##STR5## wherein Q is a hydrogen atom or a cyano group and Ris a. a cyclopropyl group of the formula ##STR6## in which R_(a) andR_(b) each is an alkyl group containing from 1 to 6 carbon atoms, or ahalogen atom having an atomic number of from 9 to 35, inclusive, or whenR_(a) is a hydrogen atom then R_(b) is an alkenyl group containing from2 to 6 carbon atoms optionally substituted by from 1 to 3 chlorine orbromine atoms, R_(c) and R_(d) each is an alkyl group containing from 1to 6 carbon atoms, or when R_(c) is hydrogen then R_(d) is an alkenylgroup having from 2 to 6 carbon atoms optionally substituted by from 1to 3 chlorine or bromine atoms or either of R_(a) and R_(b) or R_(c) andR_(d) when taken together is an alkylene group containing from 2 to 6carbon atoms; orb. a benzyl group of the fromula ##STR7## in which Z isa halogen atom having an atomic number of from 9 to 35, inclusive, or analkoxy group containing from 1 to 4 carbon atoms and Y is an alkyl groupcontaining from 1 to 6 carbon atoms, in which process an acid of theformula R--COOH in which R is as defined above is neutralized with awater-soluble base, and then contacted with a solution in awater-immiscible organic solvent of a benzyl halide of formula II##STR8## in which X is a halogen atom; and Q is as defined above in thepresence of a phase-transfer catalyst comprising a tetrahydrocarbylammonium or phosphonium halide in which the hydrocarbyl groups areselected from aromatic, aliphatic, cycloaliphatic or unsaturated groups,said groups together containing a total number of carbon atoms of from12 to
 70. 2. A process according to claim 1 wherein X represents achlorine or bromine atom.
 3. A process according to claim 1 wherein thewater-soluble base is an inorganic base.
 4. A process according to claim1 wherein the water-immiscible solvent is an organic liquid in which thebenzyl halide is at least moderately soluble.
 5. A process according toclaim 1 wherein the phase-transfer catalyst is a tetraalkylammonium ortetraalkylphosphonium halide.
 6. A process according to claim 5 whereinthe phase-transfer catalyst is selected from tetra-n-butylammoniumchloride, tetra-n-pentylammonium chloride, ethyl-tri-sec-octylammoniumchloride, ethyl-tri-n-hexylammonium chloride,n-hexadecyltri-n-hexylammonium chloride, di-n-undecyldiethylammoniumchloride, tetra-n-octylammonium chloride and benzyltri-n-butylammoniumchloride or the corresponding bromides.
 7. A process according to claim1 wherein the phenoxybenzyl ester is an alpha-cyano-3-phenoxybenzylester of tetramethylcyclopropane carboxylic acid,dimethyl-dichlorovinyl-cyclopropane carboxylic acid,dimethyl-dibromovinyl-cyclopropane carboxylic acid, or2-(4-chlorophenyl-3-methylbutyric acid and the phase-transfer catalystis a tetraalkylammonium chloride or bromide.
 8. A process according toclaim 7 wherein the water-soluble base is an inorganic base and thewater-immiscible solvent is an organic liquid in which the benzyl halideis at least moderately soluble.
 9. A process according to claim 8wherein the solvent is an organic liquid lighter than water.
 10. Aprocess according to claim 8 wherein the phenoxybenzyl ester isα-cyano-3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutyrate.
 11. Aprocess according to claim 8 wherein the phenoxybenzyl ester isα-cyano-3-phenoxybenzyl-2,2,3,3-tetramethylcyclopropane carboxylate.